It is known that certain catechol structures play an essential role as iron-complexing structural elements in natural siderophores ("Iron Transport in Microbes, Plants and Animals", Eds.: Winkelmann, G., van Helm, D., Neilands, J. B., V.Ch. Verlagsgesellschaft Weinheim, 1987), e.g. enterobactin, which is a siderophore for E. coli and other bacterial strains, is a trimer of N-(2,3-dihydroxybenzoyl)-L-serine. The monomer is also effective as a siderophore (Hantke, K., FEMS Microbiol. Lett. 67 (1990), 5).
N-(2,3-dihydroxybenzoyl)glycine has been found to be a siderophore for B. subtilis (Ito, T., Neilands, J. B., J. Amer. Chem. Soc. 80 (1958), 4645). Some catechol-substituted amino acid derivatives have already been produced synthetically, e.g. N-(2,3-dihydroxybenzoyl)-L-threonine (Kanai, F., Kaneko, T., Morishima, H., Isshiki, K., Taketa, T., Takeuchi, T., Umezawa, H., J. Antibiot. 38 (1985), 39), N.sup.2,N.sup.6 -bis-(2,3-dihydroxybenzoyl)-L-lysine (Corbin, J. L., Bulen, W. A., Biochemistry 8 (1969), 757; McKee, J. A., Sharma, S. K., Miller, M. J., Bioconjugate Chem. 2 (1991) 281), and N.sup.2,N.sup.6 -bis-(2,3-dihydroxybenzoyl)-lysyl-N.sup.6 -(2,3-dihydroxybenzoyl)lysine (Chimiak, A., Neilands, J. B., Structure and Bonding 58, (1984), 89). It is also known that certain glyoxylic acid benzhydrazones, oxanilic acid derivatives, etc., can serve as siderophores for different bacterial strains (Reissbrodt, R., Heinisch, L., Moellmann, U., Rabsch, W., Ulbricht, H., BioMetals 6 (1993), 155).
Various catechol compounds have been bonded to .beta.-lactams, by means of which an increase in the antibacterial efficacy of these antibiotics has been achieved due to their transfer into the bacterial cell via bacterial transport routes for iron (e.g. Arisawa, M., Sekine, Y., Shimizu, S., Takano, H., Angehrn, P., Then, R. L., Antimicrob. Agents Chemother. 35 (1991), 653). However, no compounds of this type have hitherto achieved their ultimate purpose of clinical application. The achievement of this object necessitates a search for new synthetic siderophores which are suitable for forming conjugates with antibiotics.
Secondly, as chelating agents for iron, siderophores are potentially capable of influencing the biological metabolism of iron, and of diseases associated therewith, in various ways. Thus the siderophore desferrioxamine B (desferal) has been successfully used in diseases which are caused by an excess of iron (e.g. thalassaemia).
Benzoxazinedione derivatives are known which have no substituent in the 8-position and which are not derived from catechol, e.g. 3-carboxymethyl-2,4-dioxobenzoxazine (e.g. Lespagnol, A., Lespagnol, Ch., Bernier, J. L., Cazin, J. C., Cazin, M., Bull. Soc. Pharm. Lille 4, (1972), 179-185). The preparation of benzoxazinedione derivatives from acyloxybenzoyl chloride and amine components with the elimination of HCl and methanol has not been described previously.